The following description includes information that may be useful in understanding the present invention. It is not an admission that any such information is prior art, or relevant, to the presently claimed inventions, or that any publication specifically or implicitly referenced is prior art.
The classical mode of administering vaccines and other pharmaceutical agents into the body tissues is by direct injection into muscle or skin tissues using a syringe and needle. As has been well disclosed in the art, incorporating electroporative pulses of electric energy with direct injection provides for delivery of such vaccines or agents directly into the cells within the tissue. Such direct delivery to cells using electroporative electric pulses can have a profound clinical effect on the quality of the response of the body's metabolic and/or immune systems over that of simple syringe and needle injection. Moreover, the capability of direct delivery of substances into the cell via electroporation has enabled the effective delivery of expressible naked DNA encoding a polypeptide, having any number of functions, including antigenic for eliciting of immune responses, or alternatively, metabolic for affecting various biologic pathways that result in a clinical effect.
Although electroporation technology allows for a more advanced delivery of substances to the cellular compartments in the body, the electroporative process, as presently commonly performed using tissue penetrating electrode arrays such as disclosed in U.S. Pat. Nos. 6,041,252, 6,278,895, and 7,245,963, has at least two distinct drawbacks for practical clinical use. These include first, the need to penetrate the skin barrier with multiple trauma inducing needles and second, no ability to easily determine the tissue volume undergoing electroporation. Classical electroporation technique, using arrays of spaced tissue-piercing needle electrodes provides for a relatively spread out area of tissue being electroporated. Typically, the tissue volume undergoing electroporation when using an array of spaced electrodes is larger than the volume bounded by the electrodes of the array. This is because of the natural flow of electric lines of force through the in vivo tissue between the positive and negative electrodes. How far around the outside of the array the elecroporative forces are capable of traveling is not easily quantifiable. This makes a quantifiable measure of the amount of drug being taken up by the cells very difficult. Thus, regarding control of therapeutic dose delivery, there remains a need to quantify the amount of tissue undergoing electroporation and consequently the dosage of drug being delivered into the cells of said tissue using electroporation.
With regard to tissue penetration, the typical spaced needle array design also causes substantial sensation of not only penetration of a multiplicity of needles into the flesh, but because of the exposed electrically conductive lengths of the penetrating electrodes the recipient of the electroporative pulse will experience a noticeable electric shock even if the upper portion of the inserted needle has a nonconductive coating. By upper portion here is meant that length of the needle that is in contact with surface and dermal tissues. Commonly, the electric pulse in the electroporation process is noticeable due to the fact that the pulse being sent between two exposed elongate electrodes sets up an electric field and an electric current through the entire depth of flesh penetrated by said electrodes. Since the skin tissues possess substantial nervous sensory cells, it is currently understood that the sensation of electric shock in the outer tissue regions is substantial. This typically unpleasant sensation is a drawback to the widespread acceptance and use of electroporation in such applications as vaccination. Further, assuming any sensation of electric shock is directly related to the tissue area or volume subject to the electric current of a certain strength, then it would reasonably appear, given that effective electroporation in a mammal is possible using only a single needle, as shown by the current inventors in co-pending patent application Ser. No. 11/894,653 herein incorporated by reference in its entirety, that use of spaced needle electrode arrays cause a far greater area of tissue to be subject to the electric pulse and consequent excitation of sensory nerve cells than is necessary. Thus, there is a need in the arts to find design configurations for delivering electroporative pulses while reducing the excitement of tissue surface and skin-based nerve cells.
Concerning the noticeable sensation of the electroporative pulse of electric energy, the level of sensation is also due in part to the design and typically bare metal nature of the electrodes used. For example, electrodes are typically constructed in various configurations such as, for example, calipers, meander electrodes, and noninvasive needle arrays for delivering an electric pulse to the surface of the skin, and underlying tissues close to the skin, and elongate and penetrating needle arrays for delivering electric pulses to deep tissue. Placement of electrodes directly onto the skin or piercing through it sets the electrode in areas of tissue where sensitivity to pain via nerve stimulation is very pronounced. Therefore, without a mechanism for lessening the current and current density in the areas of tissue having a high concentration of sensory nerve endings, the sensation of shock will likely remain.
Thus, there still exists a need in the art for electroporative methods, electrodes and systems that can provide for the ability to quantifiably measure the volume of tissue actually undergoing electroporation as well as provide for a substantial reduction in the electric energy directed in nerve sensory cell-containing tissues so as to provide for the possibility of reducing sensory cell excitement during the electroporation-assisted delivery of a therapeutic substance.